Ring b-secosteroid transformation products and process

ABSTRACT

THIS INVENTION RELATIVES TO NOVEL RING B-SECOSTEROID TRANSFORMATION PRODUCTS, TO PROCESSES FOR THEIR PREPARATION AND MORE PARTICULARLY TO COMPOUNDS EMBRACED BY THE FOLLOWING FORMULAE:   1-(HCO-),2,3-(-CH2-CH2-X-),3,10A-DI(CH3-),6-(R2-O-),8-(O=)   -1,2,3,4,4A,8,9,10,10A,10B-DECAHYDRO-6H-DIBENZO   (B,D)PYRAN (VIII) AND   1-R,2,3-(-CH2-CH2-X-),3,10A-DI(CH3-),6,8-DI(O=)-1,2,3,4,   4A,8,9,10,10A,10B-DECAHYDRO-6H-DIBENZO(B,D)PYRAN (IX)   WHEREIN R IS -CHO, -COOR1 OR -CH2OR2, IN WHICH R1 IS HYDROGEN OR METHYL AND R2 HYDROGEN OR ACYL; X IS   -CO-, -OOC-, &gt;C(-O-R2)(--R3), &gt;C(-CO-CH3)(--H),   &gt;C(-CO-CH3)(--O-R2), &gt;C(-CO-CH2-O-R2)(--O-R2) OR   (2,7-DI(R3-)-1,3,6,8-TETRAOXASPIRO(4.4)NON-4-YLIDENE   IN WHICH R2 HAS THE MEANING GIVEN ABOVE, R3 IS HYDROGEN OR LOWER-ALKYL AND THE ALKALI METAL SALTS OF THOSE COMPOUNDS WHEREIN R IS -COOR1 IN WHICH R1 IS HYDROGEN. THE COMPOUNDS OF THE ABOVE FORMULAE ARE ANTI-INFLAMMATORY AGENTS, ANTIANDROGENIC AGENTS AND CENTRAL NERVOUS SYSTEMS STIMULANTS.

United States Patent 01 fice Patented Jan. 11, 1972 3,634,460 RINGB-SECOSTEROID TRANSFORMATION PRODUCTS AND PROCESS Norman A. Nelson,Galesburg, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. NoDrawing. Filed July 28, 1969, Ser. No. 845,534 Int. (II. C0711 7/18 U.S.Cl. 260343.2 R Claims ABSTRACT OF THE DISCLOSURE This inventionrelatives to novel ring B-secosteroid transformation products, toprocesses for their preparation and more particularly to compoundsembraced by the following formulae:

wherein R is CHO, COOR or CH OR in which R is hydrogen or methyl and Rhydrogen or acyl; X is in which R has the meaning given above, R ishydrogen or lower-alkyl and the alkali metal salts of those compoundswherein R is --COOR in which R is hydrogen. The compounds of the aboveformulae are anti-inflammatory agents, antiandrogenic agents and centralnervous system stimulants.

SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION The newcompounds and the processes for their production are illustrativelyrepresented by the following sequence of formulae:

HO OH; HO

L /wi on, on, i

I Step1 V I CHO on orro VIII wherein X and R have the meanings givenherein, above;

in which R and R have the meanings given herein above; and n is theinteger 1 or 2.

In this application the term lower-alkyl means an alkyl radical of 1 to6 carbon atoms inclusive such as methyl, ethyl, propyl, butyl, amyl,hexyl and isomeric forms thereof. The term acyl means the acyl radicalof an organic carboxylic acid, preferably a hydrocarbon carboxylic acidof 1 to 12 carbon atoms, inclusive, such as acetic, propionic, butyric,isobutyric, pivalic, valeric, isovaleric, caproic, caprylic' decanoic,dodecanoic, acrylic, crotonic, hexynoic, heptynoic, octynoic,cyclobutanecarboxylic, cyclopentene-carboxylic, cyclohexane-carboxylic,dimethylcyclohexanecarboxylic, benzoic, toluic, naphthoic, ethylbenzoic,phenylacetic, naphthaleneacetic, phenylvaleric, cinnamic,phenylpropiolic, phenylpropionic, p-butoxyphenylpropionic, succinic,glutaric, dimethylglutaric, maleic, cyclopentylpropionic acids, and thelike. The wavy lines appearing in the structural formulae indicate the(alpha) configuration, the 18 (beta) configuration and mixtures thereof.

The novel compounds of Formulae VIII and IX and the alkali metal saltsthereof of those compounds, wherein R is *COOR in which R is hydrogen,are active antiinflammatory agents, anti-androgenic agents and centralnervous system stimulants.

As anti-inflammatory agents the novel compounds of this invention can beused in dosages of 05-15 mg./kg. in the treatment of gouty arthritis,rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, psoriacticarthritis, acute superficial thromobophlebitis and painful shouldersyndromes such as pertiendinitis, capsulities, bursitis, and acuteshoulder arthritis as well as contact dermatitis, atopic dermatitis,neurodermatitis, anogenital pruritus, seborrheic dermatitis, and thelike, and for the relief of pain and fever.

The novel compositions also find application in the local treatment ofinflammatory conditions in animal mastitis, a disease of the mammaryglands which can be of particular concern in milk-producing animals suchas cows.

As anti-androgenic agents the novel compounds of this invention can beused in dosages of 0.1-5 mg./kg. for the treatment of acne, hirsutism,prostatic hypertrophy and menstrual disorders.

The compounds of this invention are also active as central nervoussystem agents, useful for modulating the temperament of animals.Compounds can be administered to animals at dosages of about 1 mg./kg.of body weight to produce beneficial responses to environmental stimuliand modulation of temperament.

Suitable solid dosage forms include tablets, pills, capsules, granules,powders, suppositories, and the like. Advantageously the pharmaceuticalcarriers for such solid forms include corn starch, lactose, dicalciumphosphate, terra alba (calcium sulfate), talc, stearic acid, magnesiumstearate, and gums. Suitable fluid dosage forms include solution,suspensions, syrups, and emulsion. Advantageously, the pharmaceuticalcarrier for such fluid forms comprise water, oils, and water-oilemulsions. If desired, suitable dispersing or suspending agents can beincluded, for example, tragacanth, acacia, alginates, dextran, sodiumcarboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gelatin,and mixtures thereof. Suitable oils for solutions and water-oilemulsions include cottonseed oil, sesame oil, coconut oil, and peanutoil.

The starting materials for the process of this invention, represented byFormula I, above, are either known in the art or can be prepared fromthe corresponding A -compounds by treatment with chloranil(2,3,5,6-tetrachloro- 1,4-benzoquinone) in accordance with procedureswell known in the art, for example, Agnello et al. J. Am. Chem. Soc. 82,4293 (1960). Representative A -compounds which can be converted to thecorresponding A compounds of Formula I include, for example,

11aand llfl-hydroxytestosterone;

llaand 11B-hydroxy-androst-4-ene-3,l7-dione;

11a and 115-hydroxy-androst-4-en-3,17-dione, 17-ethylene acetal;

1141- and 1lfl-17-dihydroxy-l7a-methyltestosterone;

1100- and 1lB-hydroxyprogesterone;

1104- and llfi-hydroxyprogesterone, 20-ethylene acetal;

ketal;

1111- and 11B-hydroxytestololactone;

hydrocortisone, 7,20:20,21-bismethylenedioxy acetal;

llnc,l7oc,2l trihydroxy-4-pregnene-3,20-dione, 17,20z20,

21-bismethylenedioxy acetal;

and the like.

In instances where the llot-hydroxy starting material is not readilyavailable it can be prepared from the corresponding llfi-hydroxycompounds by methods well known in the art, for example, the protectedllfi-hydroxy compound is oxidized with chromic acid (Jones reagent) toobtain the corresponding ll-keto compound which is then converted toIla-hydroxy by a lithium-ammonia reduction.

In carrying out the process of this invention a M' -compound of FormulaI is subjected to an osmium tetroxideperiodate oxidation in accordancewith the procedures disclosed by Pappo et al., J. Org. Chem. 21, 478(1956). The selected M' -compound (I) in an inert solvent such asdioxane, tetrahydrofuran, 1.,2-dimethoxyethane and the like is subjectedto osmium tetroxide and a water soluble salt of periodic acid such assodium periodate, potassium periodate, pyridinium periodate, and thelike (sodium periodate is preferred) to obtain the compounds of FormulaII and III. Although the reaction can be carried out within a widetemperature range, such as from about 0 C. to about C.; it is preferableto carry out the reaction at about room temperature. About 15 C. toabout 35 C. is advantageous.

The compounds of Formula II and III exist in equilbrium in solution; thehemiacetal is the preponderant form and is isolated from solution inaccordance with known procedures, for example by chromatography,crystallization and the like.

The compounds of Formula III thus obtained, are then oxidized byselective oxidation with an excess of activated manganese dioxide in asuitable solvent such as chloroform, ethyl acetate, benzene, acetone,methylene chloride and the like, to obtain the corresponding compound ofFormula IV. The reaction can be carried out within the same temperaturerange as disclosed above for the osmium tetroxideperiodate reaction withabout room temperature being generally preferred. Alternatively, whenthe starting steriod material (I) is an lla-hydroxy compound, thecompounds of Formula III obtained therefrom, can be selectively oxidizedwith chromic acid, Jones reagent (a solution of 26.72 g. of chromiumtrioxide in 23 ml. of concentrated sulfuric acid diluted with Water to avolume of 100 ml.) is preferred, to obtain the corresponding oxidizedcompounds of Formula IV. When chromic acid is to be used as theoxidizing agent other oxidizable hydroxy groups present in the startingmaterial (I) should be protected by acyl groups, bismethylenedioxygroups and the like. Either a theoretical amount or an excess of oxidantcan be employed. However, to prevent oxidation of the aldehyde functionwhen an excess is used, the oxidation should be carefully controlled andfollowed, and the excess oxidant should be destroyed as soon as thedesired oxidation is complete.

The compounds of Formula IV, can then be converted to the othercompounds of this invention in accordance with methods known in the art,for example, the hydroxymethyl compounds of Formula V are prepared byreduction of the aldehyde function with sodium borohydride followed byselective oxidation with manganese dioxide of any allylic alcoholsinadvertently produced.

The compounds of Formulae HI and -IV can be converted to correspondingcarboxylic acids of Formula VI by chromic acid oxidation using an excessof oxidant, Jones reagent is preferred. If compounds III and IV containother oxidizable hydroxy groups they can be protected by conventionalmethods such as acylation as hereinafter described.

The carboxylic acids of Formula VI can be converted to theircorresponding methyl esters (VII) in accordance with known methods forexample by reaction with ethereal diazomethane in a suitable organicsolvent such as tetrahydrofuran, ether, methylene chloride, methanol ormixtures of these solvents, When the reaction is complete, the excessdiazomethane is destroyed with acetic acid and the product isolated byconventional methods. The ethylene acetal groups in the substituent X ofcompounds III, IV, V, VI and VII can be removed by a conventionalaqueous acid hydrolysis in the presence of a cosolvent such as methanol,ethanol, tetrahydrofuran, acetone, acetic acid, dioxane and the like.The acid can be p-toluenesulfonic, methanesulfonic, hydrochloric,sulfuric, formic, acetic or similar acid. It is most convenient toconduct the reaction at room temperature for 1-24 hours, but highertemperatures and shorter reaction times can be used [see DjerassiSteroid Reactions, Holden-Day 'Inc., San Francisco, 1963, pp. 17-22].The bismethylenedioxy group in the substituent X of compounds III, V, VIand VII and substituent X of compounds IX and VIII can be removed byconventional hydrolysis. For example by heating the compound in 50%aqueous acetic acid on a steam bath for 2-4 hours, or by heating thecompound with 60% aqueous formic acid at 80-100 for 5-50 min. (seeDjerassi, supra, pp. 60-61).

Acyl derivatives of the compounds of this invention are prepared inaccordance with methods commonly used for preparing steroid acylates,for example by treating the compound in pyridine with excess acidanhydride or acid chloride at about room temperature for 1-24 hours, orby heating the selected compound with an acid anhydride in the presenceof an alkali earth carbonate such as calcium carbonate. Acylating agentswhich can be employed are for example the anhydrides and chlorides ofthose acids hereinbefore listed. The excess acylating agent is destroyedby cautious addition of water to the reaction mixture at 010 and theproduct is then isolated by conventional methods.

Alkali metal salts of the carboxylic acids of Formula VI are prepared bytreating the selected compounds VI with one equivalent of aqueous sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,potassium carbonate, or potassium bicarbonate. Cosolvents such asmethanol, acetone, tetrahydrofuran and the like can be employed toinitially dissolve the acid or the acid can be extracted into theaqueous base from a water immiscible solvent such as ether, methylenechloride, chloroform, etc. The solution of carboxylic acid salt isconcentrated in vacuo to a small volume and the salt is precipitated byaddition of acetone, or the salt can be isolated by freeze drying.

The following preparation and examples illustrate the best modecontemplated by the inventior for carrying out his invention, but arenot to be construed as limiting the scope thereof.

PREPARATION 1 11a,17fl-dihydroxyandr0sta-4,6-diene-3-0ne XELOH 284 mpmax.

(6 26,200); IR and NMR spectra and consistent with the assignedstructure.

Analysis.-Calcd, for C I-1 0 (percent): C, 75.46; H, 8.67. Found(percent): C, 75.79; H, 8.77.

PREPARATION 2 11 a-hydroxypregna-4,6-diene-3,20-dione Recrystallizedchloranil (120 g.) is stirred with 120 g. of11a-hydroxy-4-pregnene-3,20-dione and 1440 ml. of t-butyl alcohol Whileheating at reflux temperature for one hour. The solvent is removed invacuo and v./v. methyl alcohol in chloroform is added. The organicsolution is washed with potassium hydroxide solution,

To a stirred mixture of 72.6 g. (0.24 mole) of 11,17 3-dihydroxy-androsta-4,6-diene-3-one, 1500 ml. of dioxane, 300 ml. ofwater, 60 ml. of pyridine and 4 g. of osmium tetroxide under a nitrogenatmosphere is added at intervals of O, 1.5 and 3.0 hr. freshly preparedsolutions of 34.2 g. (0.16 mole) of sodium metaperiodate in ml. ofwater. One hour after the last addition of periodate, a solution of 51.6g. (0.24 mole) of sodium periodate in 240 ml. of water is added followedby ml. of dioxane. The mixture is then stirred at room temperature forabout 24 hours. The reaction mixture is filtered and the collectedinorganic precipitate is washed with dioxane-absolute ethanol (4:1). Thefiltrate and washings are combined and concentrated in vacuo untilsolids begin to pre cipitate. The concentrate is extracted with two 1 l.portions of 20% ethanolchloroform and then hydrogen sulfide is thenpassed into the combined organic extracts for about 2 min. The mixtureis filtered through a pad of Celite (diatomaceous earth) and then a padof Magnesol (magnesium silicate) (92 mm. dia. x 100 mm. high) to givefiltrate A. The Magnesol pad is then washed with about 4 l. of 25%ethanol-chloroform to give filtrate B. Concentration of filtrate A invacuo and trituration of the residue with acetonitrile gives 30.6 g.(38%) of the hemiacetal, l,2,3,5,6a,7,7a,8,9,10,10a,l1,11a,11btetradecahydro-SgSp-dihydroxy-hp,1lot-dimethyl 3 oxobenz[d]indeno[5,6-b]pyran-11u carboxaldehyde, M.P. 236 C. (dec.).

Concentration of filtrate B gives 31 g. of crude residue which isdissolved in 1500 ml. of 15% ethanol-chloroform and treated with 150 g.of activated manganese dioxide. The mixture is stirred at roomtemperature for about 20 hr. and 200 ml. of ethanol is added. Themixture is filtered and the precipitate washed with about 1 l. of 25ethanol-chloroform. The filtrate and washings are combined andconcentrated in vacuo to give 24 g. of a residue which ischromatographed on a column prepared from 3 kg. of silica gel wet-packedwith 5% ethanol-chloroform. Elution of the column with 5%ethanol-chloroform gives from the first band a residue which ontrituration with acetonitrile yields 11.3 g. (14%) of lactone,1,2,3,5,6a,7, 7a,8,9,10,10a,11,l1a,1lb-tetradecahydro 8B hydroxy- 7afl,llba dimethyl 3,5 dioxobenz[d]indeno-[5,6-b]

7 pyran-llot-carboxaldehyde, M.P. 283 C. (dec.); an analytical sample ofthe lactone is crystallized from acetonitrile, M.P. 288 C. (dec.);

(6 8,800), IR, NMR and mass spectra support the assigned structure.

AnaIysis.Calcd. for C H O (percent): C, 68,65; H, 7.28. Found (percent):C, 68.42; H, 7.39.

EXAMPLE 2 1,2,3,5,6a,7,7a-,8,9,I0,10a,11,11 aJZb-tetradecahydro 8B-lzydroxy-7afi, IIba-dimethyl 3,5 dix0benz[d] indeno [5,6-b] pyran-I 1a-carboxaldehyde A mixture of 18.5 g. of the hemiacetal, from Example 1,above, 1 l. of 10% absolute ethanol-chloroform and 100 g. of activatedmanganese dioxide is stirred at room temperature for 16 hrs., and then100 ml. of absolute ethanol is added. The mixture is filtered through apad of Celite and the collected solids are washed with 20%ethanol-chloroform (ca. 1 1.). The filtrate and washings are combinedand concentrated in vacuo. Trituration of the residue with acetonitrilegives 10.2 g. of the lactone, 1,2,3, 5,6a,7,7a,8,9,10,10a,11,11a,1lbtetradecahydro 8fi-hydroxy 7aB-l1bu-dimethyl 3,5 dioxobenz[d]indeno[5,6-b]pyran-1lot-carboxaldehyde, M.P. 283 C. (dec.) and 4 g. with M.P.280 C. (dec) are obtained from the mother liquor EXAMPLE 31,2,3,5,6a,7,7a,8,9,10,10a,l1,11a,11 b-tetradecahydro 8,8-

hydroxy-7a5,l1 but-dimethyl 3,5 dioxobenz [d] indeno ,6-b] pyran-l 1ot-carboxaldehyde, acetate A mixture of 19 g. of the lactone, preparedin Example 2, above, 190 ml. of pyridine and 75 ml. of acetic anhydrideis stirred at room temperature for 16 hr., then cooled and the excessacetic anhydride is hydrolyzed by the dropwise addition of Water keepingthe temperature of the reaction mixture below 10 C. The mixture is thenshaken with chloroform and excess cold dilute hydrochloric acid. Theorganic layer is separated, washed with dilute potassium hydroxidesolution, water, dried and concentrated in vacuo. Trituration of theresidue thus obtained with acetonitrile gives 17.45 g. of1,2,3,5,6a,7,7a,8,9,10,10a,11, 1 1a,11b-tetradecahydro-8,8-hydroxy-7afl-1 lbot dimethyl-3,5-dioxobenz[d]indeno[5,6b]pyran 11a carboxaldehyde, acetate, M.P. 285C. (dec.) and a 2.45 g. second crop with M.P. 283-285 C (dec.); ananalytical sample crystallized from acetonitrile has M.P. 282284 C.(dec.),

(5 9,750); IR, NMR and mass spectra support the structure.

Armlysis.-Calcd. for C H O (percent): C, 67.36; H, 7.00. Found (percent)C, 67.53; H, 7.09.

EXAMPLE 4 1 ,2,3,5,6a,7,7a,8,9,I0,10a,11,11a,11 b-tetradecahydro 8,8-

hydroxy-7afi,lIba-dimethyl 3,5 di0xobenz[d] indeno [5 ,6-bJpyran-1 1a-carboxylic acid, acetate To a solution of. 6 g. of the product ofExample 3, above, 250 ml. of methylene chloride and 250 ml. of acetoneis added With stirring 10 ml. of Jones reagent [1. Org. Chem., 21, 1547(1956)], The reaction is allowed to proceed for about 30 min. at roomtemperature. The mixture is then diluted with 500 ml. of water andextracted with chloroform (500 ml.). The organic layers are combined,Washed with Water, dried over sodium sulfate and concentrated in vacuoto give 6 g. of 1,2,3,5, 6a,7,7a,8,9,10,10a,11,1la,llb-tetradecahydro8/3 11ydroxy-7aB,11bx dimethyl 3,5 dioxobenz(d)indeno[5,6-b]pyran-1lu-carboxylic acid, acetate, M.P. 305 C. (dec.); which isrecrystallized from dioxane to give 5.2 g. melting at 314 C. (dec.), andwhich after one additional recrystallization has a melting point of 215C. (dec.);

(6 9,950); IR, NMR and mass spectra support the structur'e.

Analysis.-Calcd. for C H O (percent): C, 64.60; H, 6.71. Found(percent): C, 64.57; H, 6.71.

EXAMPLE 5 1,2,3,5,6a,6,7, 7a,8,9,10,10a,1],11a,11 b tetradecahydro-7a}3,11b0L dimethyl 3,5 di0x0benz[d] indeno [5,6-b]

pyra'n-fla-carboxylic acid, methyl ester, acetate 0 Ac 0 Ac 1 5 i oooorr O The procedure of Example 4, above, is repeated through theextraction and concentration stepsto give 6.0 g. of crude residual1,2,3,5,6a,7,7a,8,9,10,10a,11,11a,11b-tetradecahydro8B-hydroxy-7a,8,11bot-dimethyl-3,5-dioxobenz[d]indeno[5,6-b]pyran-1la-carboxylic acid, acetate. The 6 g. of thella-carboxylic acid product thus obtained is dissolved in 700 ml. oftetrahydrofuran and ml. of methanol and treated with excess etherealdiazomethane for 5 min. The excess diazomethane is destroyed with aceticacid and the resulting mixture is concentrated in vacuo. A chloroformsolution of the residue thus obtained is washed with dilute potassiumhydroxide solution, water, dried over sodium sulfate and concentrated.The residue thus obtained is crystallized from methanol to give 4.4 g.of 1,2,3,5,6a,6,7,7a,8,9,10,102.,11,11a,1lb tetradecahydro- 7aB,11udimethyl-3,5-dioxobenz[d]indeno[5,6-b]pyran- 11oz carboxylic acid,methyl ester, acetate, M.P. 201- 202.5 C. and 1.0 g. from a 2nd cropM.P. 197 C.; an analytical sample from methanol has a melting point of203204 C.;

REEF 231 nm (6 10,450); 1R, NMR and mass spectra are in agreement withthe structure.

9 Analysis.-Calcd. for C H O (percent): C, 65.33; H, 6.98. Found(percent): C, 65.23; H, 7.08.

EXAMPLE 6 1,2,6a,7,7a,-8,9,10,Ia,11,11a,11b dodecahydr0-8;8-hydroxyIIa-(hydrOxym'ethyI) 7aB,11bot-dimethylbenz [d] indeno [5,6-b]pyran-3,5-di0ne, 8-acetate To a well-stirred suspension of 7.48 g.(0.020 mole) of the product of Example 3, above, 120 ml. of methylenechloride and 80 ml. of absolute ethanol at 0 is added a solution of 0.38g. (0.040 equiv.) of sodium borohydride in 2 ml. of water and 10 ml. ofethanol. Five minutes later 2.4 g. (0.04 mole) of acetic acid is addeddropwise and the resulting mixture is concentrated in vacuo. Absoluteethanol (100 ml.) is added to the residue and the mixture isconcentrated in vacuo to remove traces of water. The residue is thendissolved in 40 ml. of absolute ethanol and 360 ml. of chloroform and 40g. of activated manganese dioxide is added. The mixture is stirred atroom temperature for 20 hours, 100 ml. of ethanol is added and thesolids are removed by filtration. The solids thus obtained are washedwith 15% ethanol-chloroform until the washings are free of product.Concentration of the total filtrate in vacuo gives a residue which ischromatographed on a column prepared by wet packing 1.5 kg. of silicagel with 5% ethanol-chloroform. Elution with the same solvent gives aninitial band of material from which 185 mg. of starting material isobtained (from methanol) M.P. 285 C. (dec.). The second band of materialis crystallized from acetone-hexanes to give 2.05 g. of l,2,6a,7,7a,8,9,l0,l0a,11,11a,llb-dodecahydro 8fl-hydroxy 11a- (hydroxymethyl)7aB,llba-dimethylbenzyl[indeno[5,6- b]pyran-3,5-dione, S-acetate, M.P.2122l3 C.., an additional 2.6 g. of the same product, M.P. 2l1215.5 C.is recovered from the mother liquors. An analytical sample of theproduct recrystallized from ethyl acetatehexane give1,2,6a,7,7a,8,9,10,10a,11,11a,llbdodecahydro-8fl-hydroxy-1lu-(hydroxymethyl)-7a}8,llba-dimethylbenz[d]indeno[5,6-b]pyran-3,5 dione, 8 acetate, M.P. 2l3-2l4C.

max.

(a 10,000); IR, NMR and mass spectra are in agreement with thestructure.

Analysis.-Calcd. for C H O (percent): C, 67.00; H, 7.50. Found(percent): C, 67.23; H, 7.72.

EXAMPLE 7 1,2,3,5,6a,7,7a,8,9,10,10a,11,11a,]lb tetradecahydro- 5a,8fldihydroxy 7ab,l1ba-dimethyl-3-oxobenz[d] inde'no[5,6b]-pyran 11ozcarboxaldehyde, diacetate and 1,2,3,5,6a,7,7w,8,9,10,I0a,11,11a,11btetradecahydro 56,85 dihydroxy 7ab,11ba-dimethyl-3-0x0-benz[d]indeno[5,6-b] pyran-Ha carboxaldehyde, diacetate A mixture of 7g. of l,2,3,5,6a,7,7a,8,9,l0,10a,l1,1la, 1lb-tetradecahydro-5,8 8dihydroxy-7a/8,11a-dimethyl-3- oxobenz [d] indeno [5 ,6-b] pyran-llot-carboxaldehyde from Example 1, above, ml. of pyridine and 30 ml. ofacetic anhydride is stirred overnight at room temperature. The mixtureis cooled and 50 ml. of water is added dropwise keeping the temperatureof the mixture below 5 C. Ten minutes after addition of the water, themixture is shaken with chloroform and excess cold dilute hydrochloricacid. The organic layer is washed with dilute potassium hydroxidesolution and water, dried and concentrated in vacuo to give a mixture ofl,2,3,5,6a,7,7a,8,9,10,10a,l1, 1la,11b tetradecahydro5a,8fl-dihydroxy-7ab,1lba-dimethyl 3oxobenz[d]indeno[5,6-b]-pyran-llot-carboxaldehyde, diacetate andl,2,3,5,6a,7,7a,8,9,10,10a,11,11a, llb-tetradecahydro-5B,8Bdihydroxy-7ab,llba-dimethyl- 3-oxobenz[d]indeno[5,6-b] pyranlla-carboxaldehyde, diacetate. The NMR spectrum of the product indicatedthe presence of about 60% of the Sa-acetoxy isomer and 40% of theSB-acetoxy isomer.

EXAMPLE 8 8B acetyl 11a-formyl-J,2,6a,7,7a,8,9,10,10a,]1,11a,

11b dodecahydro SE-hydroxy 7115,11 bu-dimethylbenz[d]indeno[5,6-b]pyran-3,5-di0ne To a solution of 187 g. ofllet-hydroxy-4,6-pregnadiene- 3,20-dione in 3.3 l. of dioxane, ml. ofpyridine and 550 ml. of water is added 10 g. of osmium tetroxidefollowed immediately by 425 ml. of a solution of 235 g. of sodium (meta)periodate in 1010 ml. of water. The remainder of the solution is addedin two equal parts, the first addition 1.5 hr. from time zero and thesecond 3 hours from time zero (addition of osmium tetroxide). Anadditional 118 g. of sodium (meta) periodate in 500 ml. of water isadded 6 hours after time zero. After stirring overnight at roomtemperature, the solids are removed by filtration. Chloroform is addedto the filtrate and the organic layer is dried by filtration through apad of magnesium sulfate. The filtrate is treated with hydrogen sulfidegas for 10 minutes. Solids are removed by filtration through a pad ofdiatomaceous earth. The filtrate is concentrated to dryness in vacuo.The residue thus obtained is dissolved in 10% (v./v.) ethanol inchloroform and filtered through a pad of magnesium silicate (Magnesol).Elution with 30% (v./v.) ethanol in chloroform and concentration of theefliuent gives 96.2 g. of SB-acetyl- 11cc formyl1,2,6a,7,7a,8,9,10,10a,11,l1a,11b dodecahydro 55hydroxy-7afl,1lba-dimethylbenz]indeno[5, 6-b]pyran-3,5-dione, M.P.213-215 C.;

max.

8B acetyl 11a formyl 1,2,6a,7,7a,8,9,10,10a,11,11a,

11b dodecahydro 7afl,1Iboc-dimethylbenz[d] indeno- To 75 g. ofSfl-acetyl-lla-formyl-1,2,6a,7,7a,8,9,10,10a, 11,l1a,1lbdodecahydro-5g-hydroxy-7a5,1lba-dimethylbenz[d]indeno[5,6-b]pyran 3,5dione in 2.5 l. of (v./v.) ethanol in chloroform is added 225 g. ofactivated manganese dioxide. The mixture is stirred at ambienttemperature for about 24 hours, filtered and the filtrate concentratedin vacuo. Crystallization from ethyl alcohol gives 60.7 g. of thedesired lactone, 8,8-acetyl-1laformyl l,2,6a,7,7a,8,9,10,10a,l1,1la,11bdodecahydro- 7a5,1lbot dimethylbenz[d]indeno[5,6-b] pyran 3,5- dionemelting at 239-242 C. (dec.); an analytical sample melts at 241 C.(dec.) and exhibits IR and NMR spectra which are in agreement with thestructure.

Alzalysis.-Calcd. for C H O (percent): C, 70.36; H, 7.31. Found(percent): C, 69.95; H, 7.24.

EXAMPLE 10 8,8 acetyl 1,2,3,5,6afi,7,7a,8,9,10,10a,11,11a,11b-tell'adecahydro 7a/3,11lm dimethyl 3,5 dioxobenzhl] indeno[5,6-blpyran-11 OL-Clll'bOXYliC acid "To a solution of 25 g. of8,8-acetyl-11a-formyl-1,2,6a,7, 7a,8,9,l0,10a,11,lla,11b dodecahydro7afl,llba dimethylbenz[d]indeno[5,6-b]pyran-3,5-dione in 230 ml. ofacetone, and 290 ml. of methylene chloride is added 25 ml. of Jonesreagent while maintaining the temperature at about 5 C. The cooling bathis then removed and stirring is continued for about 2 hours. Isopropylalcohol is then added to destroy the excess oxidant. The mixture ispoured into ice water and methylene chloride. The organic layer isremoved, washed with Water and dried. Crystallization from ethyl acetategives 16.7 g. of the desired acid, 86 acetyl1,2,3,5,6a,8,7,7a,8,9,10,10a,ll,11a,1lb-tetradecahydro 7a/3,llbotdimethyl 3,5 dioxobenz[d] indeno[5,6-b]pyran-lla-carboxylic acid,melting at 259 261 C.;

max.

12 Analysis.Calcd. for C H O (percent): C, 67.36; H, 7.00. Found(percent): C, 66.89; H, 7.03.

EXAMPLE 11 acetyl 1,2,3,5,6aB,7,7a,8,9,10,10a,11,11a',11b tetradecahydro7afi,11ba dimethyl 3,5 di0x0benz[d] indeno [5,6-b]pyran-11zit-carboxylic acid To a cooled (5) suspension of 5 g. ofSIS-acetyl-llaformyl 1,2,6a,7,7a,8,9,10,10a,11,11a,1lb dodecahydro- 5ghydroxy 7afi,l lba-dimethylbenz[d]indeno[5,6-b]pyran-3,5-dione in 150ml. of acetone and 150 ml. of methylene chloride is added 10 ml. ofJones reagent. The cooling bath is removed and stirring continued for 3hours. The same workup as in Example 10 above is used to afford 3.4 g.of crystalline 8,8-acetyl-1,2,3,5,6aB,7,7a,8,9,10, 10a,11,11a,1lbtetrahydro-7afl,llba-dimethyl-3,5-dioxo benz [d] indeno [5 ,6-b] pyran-l1 OL-CaI'bOXYIiC acid, melting at 255-258 C.; infrared and NMR spectraare identical to those obtained upon analysis of the same productobtained in Example 10 above.

EXAMPLE 12 8 3 acetyl 1,2,3,5,6aB,7,7a,8,9,10,10a,11,11a,11btetradecahydro 7afi,11lm dimethyl 3,5di0x0benz[d]inden0[5,6-b]-pyran-11a-carboxylic acid, methyl ester Aslight excess of ethereal diazomethane is added with stirring to amixture of 6 g. of the carboxylic acid prepared in Example 11, above,ml. of methylene chloride and 100 ml. of ether. After 5 minutes ofreaction time, the excess diazomethane is destroyed by the addition of afew drops of acetic acid and the solvents are removed in vacuo. Achloroform solution of the residue thus obtained is washed with dilutehydrochloric acid, dilute potassium hydroxide solution and water. Thedried solution is concentrated in vacuo and the residue is crystallizedfrom acetonitrile to give 5.3 g. of 8B-acetyl-1,2,3,5,6a,6,7,7a,8,9,10,10a,11,1la,11b tetradecahydro 7aB, llba dimethyl 3,5dioxobenz[d]indeno[5,6-b]-pyran- Ila-carboxylic acid, methyl ester, M.P.216-217" C.; an analytical sample melted at 217218,

A212? 230 my (6 10,300); NMR, IR and mass spectra are in agreement withthe structure.

Analysis.-Calcd. for C H O (percent): C, 68.02; H, 7.27. Found(percent): C, 68.07; H, 7.31.

EXAMPLE 13 1,2,3,5,6a,7,7a,8,9,10,10a,11,11a,11 b tetradecahydro7afi,1]lm dimethyl 3,5,8 trix0benz[d] indeno [5,6-b1-pyran-1 1a-carboxaldehyde To a stirred mixture of 30.0 g. ofllfl-hydroxyandrosta- 4,6-diene-3,17-dione, 620 ml. of dioxane, 125 ml.of water, 25 ml. of pyridine and 2 g. of osmium tetroxide, under anitrogen atmosphere, is added at intervals of 0, 1.5 and 3.0 hr. freshlyprepared warm solutions of 14.25 g. of sodium periodate in 60 ml. ofwater. One hour after the last addition, a solution of 21.4 g. of sodiumperiodate in 90 ml. of water is added followed by 125 ml. of dioxane.The mixture is then stirred at room temperature for about 20 hours. Asolution of 14.25 g. of sodium periodate in 60 ml. of water is added andthe mixture is stirred for an additional period of about 24 hours. Thereaction mixture is filtered and the precipitate is washed with about250 ml. of 20% ethanol in dioxane. The filtrate and washings arecombined and concentrated in vacuo until solids begin to precipitate.The residue is extracted twice with 500 ml. of 20% ethanol inchloroform, and then hydrogen sulfide is passed into the combinedorganic extracts-for 2 minutes. The mixture is filtered through a pad ofdiatomaceous earth and then a 1 inch pad of magnesium silicate and thesolids are washed with a solution of 20% ethanol in chloroform. Thecombined filtrate and washes are concentrated in vacuo and the residueis chromatographed on a column prepared by wetpacking 3 kg. of silicagel with 8% methanol in chloroform. Elution of the column with 24%methanol in chloroform gives two principal bands. Band I contains asmall amount of unchanged starting material. Band II gives about 8.5 g.of l,2,3,5,6a,7,7a,8,9,l0,l0a,11,11a,11btetradecahydro 5 hydroxy7215,1150: dimethyl 3,8- dioxobenz[d]indeno[5,6-b]pyran 11acarboxaldehyde which is stirred with 425 ml. of chloroform and 42 g. ofmanganese dioxide for about 24 hours at which time 100 ml. of absoluteethanol is added and the mixture is filtered. Concentration of thefiltrate in vacuo gives a residue which is chromatographed on a columnprepared by Wetpacking 1 kg. of silica gel with 2 l. of 8% methanol inchloroform gives three principal bands of material. Material obtainedfrom the first band isrecrystallized from acetone to give 0.25 g. of1,2,3,5,6a,7,7a,8,9,10,10a,11, 11a,11b tetradec-ahydro 7211531 Ibo:dimethyl 3,5,8 trioxobenz[d]indeno[5,6 bJpyran 11a car-boxaldehyde, M.P.235237 C.; an analytical sample recrystallized from methylenechloride-acetone, melts at 240-243;

EtOH max.

(e 11,200); NMR, IR and mass spectra are in agreement with thestructure.

14 Analysis.Calcd. for C H O (percent): C, 69.07; H, 6.71. Found(percent): C, 69.22; H, 6.63.

I claim: 1. A compound selected from the group consisting of a compoundof the formula:

wherein R is CHO, COOR, or CH OR in which R is hydrogen or methyl and Ris hydrogen or the acyl radical of a hydrocarbon carboxylic acid of 1 to12 carbon atoms, inclusive, X is indeno-[5,6-b]pyran-1la carboxaldehyde,the compound of claim 1 wherein R is CHO; and X is in which R and R areeach hydrogen.

3. 1,2,3,5,6a,7,7a,8,9,10,10a,11,1la,11b-tetradecahydro- 8;?- hydroxy7afi,11bu dimethyl 3,5 dioxobenz[d]indeno [5 ,6-b]pyran-1la-carboxaldehyde, acetate, the compound of claim 1, wherein R is CHO;and X is (})Rs C-R in which R is acetyl and R is hydrogen.

4. 1,2,3,5,6a,7,7a,8,9,10,10a,l1,11a,11b-tetradecahydro- 8,6 hydroxy7a,fl1 lba dimethyl 3,5 dioxobenz[d]indeno[5,6-b]pyran-1lot-carboxylicacid, acetate, the compound of claim 1, wherein R is COOR in which R ishydrogen; and X is in which R is acetyl and R is hydrogen.

5. 1,2,3,5,6a,6,7,7a,8,9,10,10a,11,11a,11b tetradecahydro 7afi,11budimethyl 3,5-dioxobenz[d]indeno [5,6-b] pyran-lla carboxylic acid,methyl ester, acetate, the compound of claim 1, wherein R is COOR inwhich R is methyl; and X is (3R2 C--R in which R is acetyl and R ishydrogen.

6. 1,2,6a,7,7a,8,9,10,10a,11,11a,11b dodecahydro 8,8- hydroxy 11cc(hydroxymethyl) 7aB-,11ba-dimethylbenz[d]1ndeno[5,6-b] pyran-3,5-dione,8-acetate, the com- 15 pound of claim 1, wherein R is -CH OR in which Ris hydrogen; and X is (I)R2 C--R3 in which R is acetyl and R ishydrogen.

7. 8/3 acetyl 11o: formyl 1,2,6a,7,7a,8,9,10,10a, 11,l1a,11b dodecahydro7a/8,11ba dimethylbenz[d]indeno[5,6-b]pyran-3,5-dione, the compound ofclaim 1, wherein R is -CHO; and X is F C=O C 1--H 8. 8,3 acetyl1,2,3,5,6ap,7,7a,8,9,10,10a,11,11a,l1btetradecahydro 7a 8,1lbu dimethyl3,5 dioxobenz[d] indeno[5,6-b]pyran-1lu-carboxylic acid, the compound ofclaim 1, wherein R is COR in which R is hydrogen; and X is 9. 8B acetyl1,2,3,5,6a,8,7,7a,8,9,l0,10a,l1,1la,l1b tetradecahydro 7afi,11budimethyl 3,5 dioxobenz[d] indeno[5,6-b]pyran-1la-carboxylic acid, methylester, the compound of claim 1, wherein R is COOR in which R is methyl;and X is 10. 1,2,3,5,6a,7,7a,8,9,10,10a,11,1la,11b tetradecahydro7afl,1lba dimethyl 3,5,8 trioxobenz[d]indeno[5,6-b1pyran-1la-carboxaldehyde, the compound of claim 1, wherein R is-CHO; and X is 11. The process for the preparation of compound of theformula:

wherein X is wherein X has the meaning given above, to an osimumtetroxideperiodate oxygenation reaction to obtain the correspondinghemiacetal of the formula:

ornono wherein X has the meaning given above, and selectively oxidizingthe 5-hydroxy function of the hemiacetal so obtained with an oxidizingagent selected from the group consisting of manganese dioxide andchromic acid.

12. The process of claim 11, wherein the periodate is sodium periodateand the oxidizing agent is manganese dioxide.

13. The process of claim 2, for the preparation of1,2,3,5,6a,7,7a,8,9,10,10a,11,11a,11b tetradecahydro 8;?- hydroxy7aB,llbm-dimethyl 3,5 dioxobenz[d]indeno-[5,6-b]pyran-1lot-carboxaldehyde, wherein the starting 3- keto-A-steroid is 11a,17p-dihydroxyandrosta-4,6-diene-3- one.

14. The process of claim 12 for the preparation of 8 8- acetyl a forrnyl1,2,6a,7,7a,8,9,10,l0a,11,1la,l1bdodecahydro 7afi,11bocdimethylbenz[d]indeno[5,6-b] pyran-3,5-dione, wherein the starting3-keto-A -steroid is 1 1a-hydroxy-4,6-pregnadiene-3,20-dione.

15. The process of claim 12 for the preparation of 1,2,3,5,6a,7,7a,8,9,10,10a,1l,11a,11b tetradecahydro-7a/3,l1budimethyl 3,5,8trioxobenz[d]indeno[5,6-b]pyran 110ccarboxaldehyde, wherein the starting3-keto-A -steroid is 1 1 fl-hydroxyandrosta-4,6-diene-3, 17 -dione.

References Cited UNITED STATES PATENTS 2/1962 Abwater 260343.2 XR 6/1966Kerwin 260343.2

JOHN M. FORD, Primary Examiner US. Cl. X.R.

- v Case Na. 2651 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIONPatent No. 3, 3 460 Dated l "11 "72 Norman A. Nelson Elution of thecolumn with It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Col l5,"li ne o l, for "chloroform gives read "chloroform.

2 5 methanol in chloroform gives-- Col 16, line 58, for Claim 2" readClaim 12".

Signed and sealed this 27th day of June 1972.

(SEAL) 'Attest: v

EDWARD M.FLETCHER,JR. I v ROBERT GO'I'TSCHALK v Comissioner of PatentsAttesting Officer USCOMM-DC 60376-P69 a: u.s GOVERNMENT PRINTING OFFICE:1969 0-356-314 FORM PO-1050 (10-69)

